Photodynamic Therapy Of Cancer

Photodynamic therapy (PDT) of cancer is based on the use of compounds that are able to absorb harmless visible light energy and transfer it efficiently to other molecules in their vicinity or alternatively use it for photochemical reactions with biomolecules.100 These compounds are normally known as photosensitizers (PS). After irradiation with light of the suitable wavelength, the PS molecules are excited from the ground state (1PS0) to a singlet excited state (1PS*) that can reverse to the ground state by nonradiative internal crossing (IC) or by fluorescent emission (F), the latter of which can be used for imaging and detection (photo-diagnosis). Alternatively, it may undergo an electronic rearrangement to the excited triplet state (3PS*) by intersystem crossing (ISC, Fig. 4.45). Most reactions of relevance to PDT take place in the triplet state, which must be sufficiently long-lived to give intermolecular reactions before its deactivation by emission of phosphorescence (P). In the Type 1 reactions, the PS triplet state reacts with an organic molecule (e.g., a component of the cell membrane) and transfers an electron to form a radical. These radicals may react further with oxygen, giving superoxide and other ROS. In Type 2 reactions, the PS triplet state transfers its energy directly to oxygen, leading to the formation of excited state singlet oxygen, a very potent oxidizer that is believed to be the main damaging agent acting by nonspecific oxidation of intracellular targets. The efficiency of these processes can be improved by increasing the stability of the triplet state, which can be achieved by spin-orbit coupling. In more familiar chemical terms, this involves the inclusion of heavy atoms in the structure of the photosensitizer, for example, by replacement of oxygen by sulfur, sulfur by selenium, or hydrogen by bromine or iodine.

Among the many compounds studied,101 only two classes have been approved for clinical use, namely porphyrins and psoralens, although most work on PDT has been carried out with porphyrin-based drugs. One major problem of PDT is the lack of selective accumulation of photoactivable molecules within tumor tissues, and for this reason the development of targeted photosensitizers is an active research area.102

Initial preparations of hematoporphyrin were complex mixtures of porphyrin oligomers, which were later replaced by photophrin (porfimer sodium oligomer), which has a more regular composition.1 3 The semisynthetic derivative talapor-phin (mono-l-aspartylchlorin e6) has been approved for early stage lung cancer and, compared with other photosensitizers, it has the advantage of its high aqueous solubility and of being associated with minimum cutaneous photosensitivity. It has a long activation wavelength of 664 nm (in the red part of the visible spectrum), allowing deeper tissue penetration (Fig. 4.46).104

An alternative treatment that has also been used in the clinic involves the use of 5-aminolevulinic acid (ALA), a biosynthetic precursor of the natural photosen-sitizer protoporphirin IX (Fig. 4.47). This compound is normally employed as ester prodrugs, which have an improved absorption when administered as creams.105 Protoporphyrine thus generated is selectively accumulated in some tumors because of their accelerated metabolism, which includes a faster processing of ALA.

After administration of the photodynamic agent, selective irradiation of the target tissue is achieved by use of a fiber optic diffuser inserted through an endoscope, which leads to local activation. Because of the low stability of the toxic species involved, diffusion to surrounding healthy tissues is not significant and therefore the method is minimally invasive and is well tolerated, although there are obvious limitations in light delivery to the tumor.

Porphyrin-based PDT has been in clinical use for about 20 years, initially for skin cancers. Subsequently it has established itself as a therapeutic strategy for

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